Chemical process

ABSTRACT

The present invention provides a novel chemical process for the synthesis of the compound N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxpyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide.

FIELD OF INVENTION

The present invention relates to a novel chemical process for the synthesis of the compound N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide.

BACKGROUND OF THE INVENTION

The compound N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide, herein also referred as compound of formula (1),

is a BCR-ABL (breakpoint cluster region-Abelson chimeric protein) tyrosine-kinase inhibitor. WO 2013/171639 A1 provides compounds of Formula (1) as useful in treating diseases which respond to inhibition of the tyrosine kinase enzymatic activity of the Abelson protein (ABL1), the Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1. The compound of Formula (1) is also known as (R)—N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide, or asciminib.

The compound of Formula (1), preparation of the compound of formula (1), and pharmaceutical compositions of the compound of formula (1) are originally described in WO 2013/171639 A1 as Example 9.

Nevertheless, there remains a need to provide improved processes for the preparation of the compound of formula (1), which are economically more efficient, safer, and better suited for full size production scale.

DESCRIPTION OF THE INVENTION

The present invention is directed to an improved synthesis of compound of formula (1) and its purification, using less hazardous chemicals and/or reaction conditions, generating less waste and providing a reproducible process that is easier to handle on production scale. The present invention is also directed to a more efficient means of generating the compound of formula (1) at higher yield and in higher purity, generates less byproducts, and requires a lower catalyst loading compared to the methods disclosed in the prior art.

In this regard, the present invention is provided in the following aspects.

In accordance with a first aspect of the present invention, there is provided a process for producing the compound of formula (1),

-   -   or a salt, solvate, stereoisomer, complex, co-crystal, ester, or         oxazoline thereof, comprising the step of reacting the compound         of formula (2),

-   -   or a salt, solvate, stereoisomer, complex, co-crystal, ester or         oxazoline thereof;

and the compound of formula (3),

or 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid, pinacol ester with an alkali or alkaline salt in the presence of a metal complex catalyst to obtain the compound of formula (1) or a salt, solvate, stereoisomer, complex, co-crystal, ester or oxazoline thereof, preferably to obtain compound of formula (1) is in its free carboxylic acid form.

In the process, according to first aspect, the metal complex catalyst may be a metal precursor and a ligand or a pre-formed metal complex catalyst comprising a metal M and a ligand.

The metal M may be selected from Cu (copper) and Pd (palladium). Preferably the metal M is Pd.

The metal precursor may be selected from M(OAc)₂, M₂(dba)₃, [M(C₃H₅)Cl]₂ (allyl metal chloride dimer), M(TFA)₂, M(MeCN)₂Cl₂, MCl₂, [(cinnamyl)MCl]₂, [MCl]₂ (metal chloride), and M(acac)₂. Preferably the metal precursor is [MCl]₂ (metal chloride).

The ligand may be selected from Cy₃P, (2-MeOPh)₃P, P(tBu)₂-n-PrSO₂H, Q-phos (1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene), CataCXium ABn (Di(1-adamantyl)benzylphosphine), CataCXium A (Di(1-adamantyl)-n-butylphosphine), and S-Phos (2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl). Preferably, the ligand is S-Phos.

The pre-formed metal complex catalyst may be composed of the metals as ligands as defined above or is selected from [(o-tol)₃P]₂PdCl₂, [t-Bu₃PPdBr]₂/Pd-113, (dtbpf)PdCl₂/Pd-118, PEPPSI, PdCl₂(PPh₃)₂, Pd(tBu₂PhP)₂, Pd(dppf)Cl₂.CH₂Cl₂, [(t-Bu)₃P]Pd(0), CataCXium C, Pd(tBu₂PhP)₂(Pd-122), Pd(dppf)Cl₂—CH₂Cl₂ (Pd-106), (2-MeOPh)₃P/Pd₂(dba)₃, and PdCl₂(Amphos)₂/Pd-132. Preferably, the pre-formed metal complex catalyst is selected from (dtbpf)PdCl₂ (Pd-118), Pd(tBu₂PhP)₂(Pd-122), Pd(dppf)Cl₂—CH₂Cl₂ (Pd-106) and (2-MeOPh)₃P/Pd₂(dba)₃.

The alkali or alkaline salt may be selected from Na₂CO₃, C_(s)2CO₃, K₃PO₄, KF, and K₂CO₃. Preferably, the alkaline salt is K₂CO₃.

WO 2013/171639 A1, Example 9 describes a similar process in Stage 9.5 whereby the pre-formed metal complex catalyst Pd(PPh₃)₂Cl₂ and alkali salt K₃PO₄ in toluene are used to yield intermediate methyl 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinate. However, when scaled up to 3 kg, the synthesis resulted in incomplete conversion of starting materials and required additional amounts of the compound of formula (3) and K₃PO₄ to complete the reaction, thus not suitable for large scale manufacturing of the compound of formula (1).

The reaction provided herein provides a high rate of conversion [>98%, conversion to the compound of formula (1)] and a high purity [>96% purity measured as in-process control (IPC)]. The compound of formula (1) is obtained in high yield (>80%).

An advantage of this process over the prior art process is the reduction of byproducts produced and catalyst loading required for a more complete conversion of starting materials. Therefore, the process of the invention suitable for scaling up for commercial production purposes.

In accordance with a second aspect of the invention, there is provided the process according to first aspect, further comprising the step of reacting the compound of formula (4)

or a salt, solvate, stereoisomer, complex, co-crystal, ester or oxazoline thereof, preferably the compound of formula (4) is in its free methyl ester form; with the compound of formula (5),

to obtain the compound of formula (6)

or a salt, solvate, stereoisomer, complex, co-crystal, ester or oxazoline thereof, preferably the compound of formula (6) is in its free carboxylic acid form.

WO 2013/171639 A1, Example 9 describes a similar process in alternate Stage 9.1 by substituting a compound of formula (4) with 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinic acid in NMM and combining with HOBt.H₂O and EDCl.HCl in THF. However, 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinic acid was found difficult to crystallize, extract, and deliver consistent yield from the reaction. The synthesis also resulted in problematic impurities that are difficult to eliminate and negatively impacted yield.

An advantage of the process disclosed herein over the prior art process is that it avoids the problems found with 6-((R)-3-hydroxpyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinic acid and delivers consistent yield of the compound of formula (6). Therefore, the process of the invention is suitable for scaling up for commercial production purposes.

EXAMPLES Example 1: Step D2+D3->D4

Basic Procedure:

A mixture of (R)-methyl 5-bromo-6-(3-hydroxypyrrolidin-1-yl)nicotinate (45.6 kg, D2), 1-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid, pinacol ester (50.5 kg, D3), and K₂CO₃ (41.8 kg) in toluene (282 mL) was added to a dry vessel. The suspension was stirred and water was added. PdCl₂(dtbpf) (500 g) was added and the suspension was stirred at about 50° C. until full conversion was achieved. After reaction completion, QuadraSil MP was added to the reaction mixture. The solid residues were removed by filtration over activated charcoal filter and the filter residue was washed with toluene, potable water and again with toluene. The organic and aqueous phases were separated and the aqueous layer was washed with toluene. The combined organic layers were washed with sodium chloride solution, dried using [Na₂SO₄] and evaporated in situ to provide methyl 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinate (D4). Yield of D4 was estimated to be about 54 kg D4/kg D2 (˜95%).

Example 2: Step D4+D5->D6

To an empty vessel, a solution of sodium hydroxide (15.8 kg) and water was added to a mixture of 31.6 kg 4-(chlorodifluoromethoxy)aniline HCl (D5) in methyltetrahydrofuran (344 kg) and the reaction mixture was stirred at around 25° C. The biphasic mixture was separated and the organic phase was washed twice with water. The organic phase was concentrated by distillation, followed by addition of fresh methyltetrahydrofuran (2×148 kg) to obtain a concentrated solution of 4-(chlorodifluoromethoxy)aniline in methyltetrahydrofuran.

To the 10-20% solution of 660 kg of methyl 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinate (D4) in toluene, methyltetrahydrofuran (239 kg) was added and the solution was concentrated by distillation. To this concentrated solution, 148 kg of concentrated solution of D5 in methyltetrahydrofuran was added. To the obtained a mixture, 20% potassium tert-butoxide (258 kg) in tetrahydrofuran (169 kg) was dosed at around 25° C. After reaction completion, aqueous sodium chloride solution (602 kg) was added and biphasic mixture was separated. The organic phase was extracted with aqueous sodium chloride (602 kg) solution. The organic layer was filtered over activated charcoal filter. The solvent was exchanged by distillation from methyltetrahydrofuran to isopropanol. To this solution, seed crystals of N-(4-(Chlorodifluoromethoxy)phenyl)-6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (0.16 kg, D6) were added, followed by n-heptane (1274 kg). D6 was collected by filtration, washed with a mixture of n-heptane and isopropanol and dried under vacuum. Yield of D6 was estimated to be about 79-87% of D6 based on amount of D3 charged.

Example 3: Step D6->A1

To a suspension of N-(4-(Chlorodifluoromethoxy)phenyl)-6-((R)-3-hydroxpyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (39.1 kg, D6) in methanol (346 kg), 37% HCl solution (9 kg) was added at 22° C. (pH<1). The clear solution was then stirred for 1 h at 22° C. (IPC). The mixture was then quenched with 30% NaOH (4 kg) (pH=10). Water was added to the mixture and the pH was adjusted to 2.5 to 3.0 by the addition of 30% NaOH. The solution was filtered over an active charcoal filter and then the pH was adjusted to 3.0-3.5 by the addition of more 30% sodium hydroxide before seeding with N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxpyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide (0.027 kg, A1. A final pH adjustment to pH 7.5-9.0 was performed by the addition of ca. 1% sodium hydroxide solution resulting in precipitation of the product. The suspension was cooled to 10° C. and stirred before the product A1 was isolated by filtration, washed with a 4:1 mixture of water/methanol and dried. Yield of A1 was estimated to be about 76%.

Example 4: A1->A1a

A mixture of N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxpyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide (29.2 kg, A1), methanol (190 kg), and 37% hydrochloric acid (7 kg) is heated to about 50° C. and the resulting solution was filtered. The first portion of t-butyl methyl ether TBME (146 kg) and seed crystals of N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide hydrochloride (0.26 kg, Ala) were added at about 50° C. to the filtrate. The second portion of TBME (271 kg) was added and the suspension cooled to about 0° C. and stirred to allow for completion of crystallization. Ala was collected by filtration, washed with a mixture of TBME (78 kg) and methanol (9 kg) and dried under vacuum. Yield of Ala was estimated to be about 96%. 

1. A process for producing the compound of formula (1),

or a salt, solvate, stereoisomer, complex, co-crystal, ester, or oxazoline thereof, comprising the step of reacting the compound of formula (2),

or a salt, solvate, stereoisomer, complex, co-crystal, ester or oxazoline thereof; and the compound of formula (3),

with an alkali or alkaline salt in the presence of a metal complex catalyst to obtain the compound of formula (1) or a salt, solvate, stereoisomer, complex, co-crystal, ester or oxazoline thereof.
 2. The process according to claim 1, wherein the metal complex catalyst is a metal precursor and a ligand or is a pre-formed metal complex catalyst comprising a metal M and a ligand, and wherein the metal M is selected from Cu and Pd; wherein the metal precursor is selected from M(OAc)₂, M₂(dba)₃, [M(C₃H₅)Cl]₂ (allyl metal chloride dimer), M(TFA)₂, M(MeCN)₂Cl₂, MCl₂, [(cinnamyl)MCl]₂, and M(acac)₂; wherein the ligand is selected from Cy₃P, (2-MeOPh)₃P, P(tBu)₂-n-PrSO₂H, Q-phos, CataCXium ABn, CataCXium A and S-Phos; wherein the pre-formed metal complex catalyst is composed of the metals as ligands as defined above or is selected from [(o-tol)₃F]₂PdCl₂, [t-Bu₃PPdBr]₂/Pd-113, (dtbpf)PdCl₂/Pd-118, PEPPSI, PdCl₂(PPh₃)₂, Pd(tBu₂PhP)₂/PD-122, Pd(dppf)Cl₂.CH₂Cl₂/PD-106, [(t-Bu)₃P]Pd(0), CataCXium C, PdCl₂(Amphos)₂/Pd-132, (2-MeOPh)₃P/Pd₂(dba)₃, and S-Phos Pd(OAc)₂; and wherein the alkali or alkaline salt is selected from Na₂CO₃, C_(s)2CO₃, K₃PO₄, KF and K₂CO₃.
 3. A process according to claim 1 or 2, further comprising the step of reacting the compound of formula (4),

or a salt, solvate, stereoisomer, complex, co-crystal, ester or oxazoline thereof, with the compound of formula (5),

or a salt, solvate, stereoisomer, complex, co-crystal, ester or oxazoline thereof. 